US5418240A - Heterocyclic compounds and their preparation and use - Google Patents

Heterocyclic compounds and their preparation and use Download PDF

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Publication number
US5418240A
US5418240A US08/026,943 US2694393A US5418240A US 5418240 A US5418240 A US 5418240A US 2694393 A US2694393 A US 2694393A US 5418240 A US5418240 A US 5418240A
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United States
Prior art keywords
compounds
branched
straight
compound
formula
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Expired - Lifetime
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US08/026,943
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English (en)
Inventor
Per Sauerberg
Preben H. Olesen
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Novo Nordisk AS
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Novo Nordisk AS
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Filing date
Publication date
Priority claimed from DK198590A external-priority patent/DK198590D0/da
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to US08/026,943 priority Critical patent/US5418240A/en
Assigned to NOVO NORDISK A/S reassignment NOVO NORDISK A/S ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OLESEN, PREBEN H., SAUERBERG, PER
Priority to TW083101718A priority patent/TW350846B/zh
Priority to US08/204,832 priority patent/US5527813A/en
Priority to CA002157579A priority patent/CA2157579C/en
Priority to DK94908990T priority patent/DK0687266T3/da
Priority to HU9502588A priority patent/HUT72443A/hu
Priority to SK1101-95A priority patent/SK281005B6/sk
Priority to ES94908990T priority patent/ES2126099T3/es
Priority to AT94908990T priority patent/ATE173257T1/de
Priority to ZA941542A priority patent/ZA941542B/xx
Priority to JP51948094A priority patent/JP3411923B2/ja
Priority to EP94908990A priority patent/EP0687266B1/de
Priority to PCT/DK1994/000092 priority patent/WO1994020496A1/en
Priority to CN94191810A priority patent/CN1046722C/zh
Priority to CZ19952251A priority patent/CZ290639B6/cs
Priority to NZ262372A priority patent/NZ262372A/en
Priority to AU62027/94A priority patent/AU694415B2/en
Priority to DE69414554T priority patent/DE69414554T2/de
Priority to PH47880A priority patent/PH31394A/en
Priority to KR1019950703745A priority patent/KR100344329B1/ko
Priority to IL10886594A priority patent/IL108865A/xx
Publication of US5418240A publication Critical patent/US5418240A/en
Application granted granted Critical
Priority to US08/450,838 priority patent/US5578602A/en
Priority to US08/450,107 priority patent/US5641791A/en
Priority to US08/452,033 priority patent/US5574043A/en
Priority to FI954130A priority patent/FI954130A/fi
Priority to NO19953491A priority patent/NO312676B1/no
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to therapeutically active azabicyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds.
  • novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.
  • Alzheimer's disease a pathophysiological disease known as Alzheimer's disease. This disease is combined with, and also most likely caused by, a up to 90% degeneration of the muscarinic cholinergic neurons in nucleus basalis, which is part of substantia innominata. These neurons project to the prefrontal cortex and hippocampus and have a general stimulatory effect on the cognitive functions of the forebrain as well as of hippocampus, namely learning, association, consolidation and recognition.
  • muscarinic cholinergic agonists are useful in the treatment of Alzheimer's disease and in improving the cognitive functions of elderly people.
  • arecoline methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate
  • cholinergic agonist methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate
  • Arecoline however has a very short biological half life and a small separation between central and peripheral muscarinic effects. Furthermore arecoline is a rather toxic compound.
  • EP-A-0307142 discloses a class of thiadiazoles, substituted on one of the ring carbon atoms with a non-aromatic azacyclic or azabicyclic ring system, and substituted on the other ring carbon atom with a substituent of low lipophilicity, or a hydrocarbon substituent, which are muscarinic agonists and therefore useful in the treatment of neurological and mental illnesses and severe painful conditions.
  • novel compounds of the invention are heterocyclic compounds having the formula I ##STR1## wherein X is oxygen or sulphur;
  • R is halogen, --CHO, --NO 2 , --OR 4 , --SR 4 , --SOR 4 and --SO 2 R 4 , wherein R 4 is straight or branched C 1-15 -alkyl, straight or branched C 2-15 -alkenyl, straight or branched C 2-15 -alkynyl, optionally substituted with one or more halogen(s), --CF 3 , --CN, phenyl or phenoxy wherein the phenyl or phenoxy group may be optionally substituted with halogen, --CN, C 1-4 -alkyl or C 1-4 -alkoxy, or a phenyl or benzyloxycarbonyl group each of which may be optionally substituted with halogen, --CN, C 1-4 -alkyl or C 1-4 -alkoxy, or --OR 5 Y, --SR 5 Y, --OR 5 ZY, --SR 5 ZY, wherein Z is oxygen or sulphur, R 5 is straight or
  • G is selected from one of the following azabicyclic rings ##STR2## wherein the thiadiazole or oxadiazole ring can be attached at any carbon atom of the azabicyclic ring; R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1-5 -alkyl, straight or branched 2-5 -alkenyl, straight or branched C 2-5 -alkenyl, straight or branched C 1-10 -alkoxy, straight or branched C 1-5 -alkyl substituted with --OH, --OH, halogen, --NH 2 or carboxy; R 3 is H, straight or branched C 1-5 -alkyl, straight or branched C 2-5 -alkenyl or straight or branched C 2-5 -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salt.
  • the compounds of this invention are also useful analgesic agents and therefore useful in the treatment of severe painful conditions.
  • the compounds of this invention are useful in the treatment of glaucoma.
  • the invention also relates to methods of preparing the above mentioned compounds, comprising:
  • the pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3 H-Oxotremorine-M ( 3 H-Oxo). Birdsdall N. J. M., Hulme E. C., and Burgen A. S. V. (1980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain”. Proc. Roy. Soc. London (Series B) 207,1.
  • 3 H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors).
  • Three different sites are labelled by 3 H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
  • the inhibitory effects of compounds on 3 H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.
  • Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenized for 5-10 s in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined suspension centrifuged for 15 min at 40,000 ⁇ g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 ⁇ 10 ml of buffer and centrifuged for 10 min at 40,000 ⁇ g.
  • the final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 ⁇ l of test solution and 25 ⁇ l of 3 H-Oxotremorine (1.0 nM, final concentration) mixed and incubated for 30 min at 25° C. Non-specific binding is determined in triplicate using arecoline (1 ⁇ g/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fibre filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
  • Test substances are dissolved in 10 ml water (if necessary heated on a steam bath for less than 5 minutes) at a concentration of 2.2 mg/ml. 25-75% inhibition of specific binding must be obtained before calculation of IC 50 .
  • IC 50 the concentration (ng/ml) of the test substance which inhibits the specific binding of 3 H-Oxo by 50%.
  • IC 50 the concentration (ng/ml) of the test substance which inhibits the specific binding of 3 H-Oxo by 50%.
  • the compounds of the invention together with a conventional adjuvant, carrier, or diluent, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective muscarinic cholinergic agonistic amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance with conventional methods of galenic pharmacy.
  • excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or enteral application which do not deleteriously react with the active compounds.
  • Such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Ampoules are convenient unit dosage forms. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch, are particularly suitable for oral application.
  • a syrup, elixir of the like can be used in cases where a sweetened vehicle can be employed.
  • the compounds of this invention are dispensed in unit form comprising 1-100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 1-100 mg/day, preferably 10-70 mg/day, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains:
  • the compounds of the invention are extremely useful in the treatment symptoms related to a reduction of the cognitive functions of the brain of mammals, when administered in an amount effective for stimulating the cognitive functions of the forebrain and hippocampus.
  • the important stimulating activity of the compounds of the invention includes both activity against the pathophysiological disease, Alzheimer's disease as well as against normal degeneration of brain function.
  • the compounds of the invention may accordingly be administered to a subject, e.g., a living animal body, including a human, in need of stimulation of the cognitive functions of the forebrain and hippocampus, and if desired in the form of a pharmaceutically acceptable acid addition salt thereof (such as the hydrobromide, hydrochloride, or sulfate, in any event prepared in the usual or conventional manner, e.g., evaporation to dryness of the free base in solution together with the acid), ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective forebrain and hippocampus stimulating amount, and in any event an amount which is effective for improving the cognitive function of mammals due to their muscarinic cholinergic receptor agonistic activity.
  • a pharmaceutically acceptable acid addition salt thereof such as the hydrobromide, hydrochloride, or
  • Suitable dosage ranges are 1-100 milligrams daily, 10-100 milligrams daily, and especially 30-70 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)
US08/026,943 1990-08-21 1993-03-05 Heterocyclic compounds and their preparation and use Expired - Lifetime US5418240A (en)

Priority Applications (26)

Application Number Priority Date Filing Date Title
US08/026,943 US5418240A (en) 1990-08-21 1993-03-05 Heterocyclic compounds and their preparation and use
TW083101718A TW350846B (en) 1993-03-05 1994-02-28 1,2,5-thiadiazol substituted azabicyclic compounds and their preparation and use as muscarinic cholinergic agonists
US08/204,832 US5527813A (en) 1990-08-21 1994-03-02 Heterocyclic compounds and their preparation and use
IL10886594A IL108865A (en) 1993-03-05 1994-03-04 Azabicyclic compounds their preparation and pharmaceutical compositions comprising them
CN94191810A CN1046722C (zh) 1993-03-05 1994-03-04 杂环化合物及其制备和应用
AU62027/94A AU694415B2 (en) 1993-03-05 1994-03-04 Heterocyclic compounds and their preparation and use
HU9502588A HUT72443A (en) 1993-03-05 1994-03-04 Heterocyclic compounds and their preparation and use
SK1101-95A SK281005B6 (sk) 1993-03-05 1994-03-04 Azabicyklické zlúčeniny, ich použitie a farmaceutická kompozícia s ich obsahom
ES94908990T ES2126099T3 (es) 1993-03-05 1994-03-04 Compuestos heterociclicos y su preparacion y uso.
AT94908990T ATE173257T1 (de) 1993-03-05 1994-03-04 Heterocyclische verbindungen und ihre herstellung und verwendung
ZA941542A ZA941542B (en) 1993-03-05 1994-03-04 Heterocyclic compounds their use and preparation
JP51948094A JP3411923B2 (ja) 1993-03-05 1994-03-04 複素環式化合物及びその調製と使用
EP94908990A EP0687266B1 (de) 1993-03-05 1994-03-04 Heterocyclische verbindungen und ihre herstellung und verwendung
PCT/DK1994/000092 WO1994020496A1 (en) 1993-03-05 1994-03-04 Heterocyclic compounds and their preparation and use
CA002157579A CA2157579C (en) 1993-03-05 1994-03-04 Heterocyclic compounds, their use and preparation
CZ19952251A CZ290639B6 (cs) 1993-03-05 1994-03-04 Azabicyklické sloučeniny a farmaceutický prostředek je obsahující
NZ262372A NZ262372A (en) 1993-03-05 1994-03-04 Oxa (or thia) diazole-subststituted 1-azabicyclo derivatives
DK94908990T DK0687266T3 (da) 1993-03-05 1994-03-04 Heterocykliske forbindelser og deres fremstilling og anvendelse
DE69414554T DE69414554T2 (de) 1993-03-05 1994-03-04 Heterocyclische verbindungen und ihre herstellung und verwendung
PH47880A PH31394A (en) 1993-03-05 1994-03-04 Certain Ä,2,5-thiadiazol-4-ylÜ-1-azabicyclo Ä3,2,1Üoctane derivaives and their pharmaceutical uses.
KR1019950703745A KR100344329B1 (ko) 1993-03-05 1994-03-04 아자비사이클릭화합물,이의제조방법및이를함유하는약제학적조성물
US08/450,107 US5641791A (en) 1991-08-13 1995-05-25 Heterocyclic compounds and their preparation and use
US08/450,838 US5578602A (en) 1990-08-21 1995-05-25 Certain 1-azabicyclo[3.3.1]nonene derivatives and their pharmacological uses
US08/452,033 US5574043A (en) 1991-08-13 1995-05-26 Certain [1,2,5-thiadiazol-4-yl]-1-azabicyclo [3.2.1]octane derivatives and their pharmaceutical uses
FI954130A FI954130A (fi) 1993-03-05 1995-09-04 Heterosykliset yhdisteet ja niiden valmistus ja käyttö
NO19953491A NO312676B1 (no) 1993-03-05 1995-09-05 Azabisyklisk substituerte tiadiazolforbindelser, fremgangsmåte for fremstilling derav, farmasöytiske preparater oganvendelse av forbindelsene til fremstilling av medikamenter

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK1985/90 1990-08-21
DK198590A DK198590D0 (da) 1990-08-21 1990-08-21 Heterocykliske forbindelser, deres fremstilling og anvendelse
US07/744,160 US5260314A (en) 1990-08-21 1991-08-13 Certain 3-(1,2,5-oxa- or thiadiazol-4-yl)-1-azabicyclo [2.2.2]octanes having pharmaceutical properties
US08/026,943 US5418240A (en) 1990-08-21 1993-03-05 Heterocyclic compounds and their preparation and use

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US07/744,160 Continuation-In-Part US5260314A (en) 1990-08-21 1991-08-13 Certain 3-(1,2,5-oxa- or thiadiazol-4-yl)-1-azabicyclo [2.2.2]octanes having pharmaceutical properties

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US08/204,832 Continuation-In-Part US5527813A (en) 1990-08-21 1994-03-02 Heterocyclic compounds and their preparation and use

Publications (1)

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US5418240A true US5418240A (en) 1995-05-23

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US08/026,943 Expired - Lifetime US5418240A (en) 1990-08-21 1993-03-05 Heterocyclic compounds and their preparation and use

Country Status (21)

Country Link
US (1) US5418240A (de)
EP (1) EP0687266B1 (de)
JP (1) JP3411923B2 (de)
KR (1) KR100344329B1 (de)
CN (1) CN1046722C (de)
AT (1) ATE173257T1 (de)
AU (1) AU694415B2 (de)
CZ (1) CZ290639B6 (de)
DE (1) DE69414554T2 (de)
DK (1) DK0687266T3 (de)
ES (1) ES2126099T3 (de)
FI (1) FI954130A (de)
HU (1) HUT72443A (de)
IL (1) IL108865A (de)
NO (1) NO312676B1 (de)
NZ (1) NZ262372A (de)
PH (1) PH31394A (de)
SK (1) SK281005B6 (de)
TW (1) TW350846B (de)
WO (1) WO1994020496A1 (de)
ZA (1) ZA941542B (de)

Cited By (14)

* Cited by examiner, † Cited by third party
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US5574043A (en) * 1991-08-13 1996-11-12 Novo Nordisk A/S Certain [1,2,5-thiadiazol-4-yl]-1-azabicyclo [3.2.1]octane derivatives and their pharmaceutical uses
US5641791A (en) * 1991-08-13 1997-06-24 Novo Nordisk A.S Heterocyclic compounds and their preparation and use
US6596869B2 (en) 1992-02-20 2003-07-22 Smithkline Beecham Plc Nitrosation process
US5968926A (en) * 1993-08-19 1999-10-19 Novo Nordisk A/S Antipsychotic method
US5663182A (en) * 1993-08-19 1997-09-02 Bymaster; Franklin Porter Antipsychotic method
US5773619A (en) * 1994-05-14 1998-06-30 Smithkline Beecham P.L.C. Process for the preparation of azabicycloc derivatives
US6194416B1 (en) 1994-10-24 2001-02-27 Eli Lilly And Company Heterocyclic compounds and their use
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US5605908A (en) * 1994-10-24 1997-02-25 Eli Lilly And Company Heterocyclic compounds and their use
US5998404A (en) * 1994-10-24 1999-12-07 Eli Lilly And Company Heterocyclic compounds and their use
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US5750538A (en) * 1996-01-04 1998-05-12 Novo Nordisk A/S Method of treating hypercholesterolemia and related disorders
US6284771B1 (en) * 1997-04-11 2001-09-04 Eli Lilly And Company Method for treating schizophrenia
WO1998046227A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Composition for treating pain
WO1998046226A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Method for treating schizophrenia
WO1998054151A1 (en) * 1997-05-29 1998-12-03 Eli Lilly And Company Process for preparing heterocyclic compounds
US20030092694A1 (en) * 1999-05-21 2003-05-15 Biovitrum, Ab, A Stockholm, Sweden Corporation Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
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WO2002015906A1 (en) * 2000-08-21 2002-02-28 Georgetown University 2-3-disubstituted quinuclidines as modulators of monoamine transporters and therapeutic and diagnostic methods based thereon
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EP0687266A1 (de) 1995-12-20
HUT72443A (en) 1996-04-29
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AU6202794A (en) 1994-09-26
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FI954130A0 (fi) 1995-09-04
CN1046722C (zh) 1999-11-24
NO953491D0 (no) 1995-09-05
IL108865A0 (en) 1994-06-24
CZ225195A3 (en) 1996-04-17
ATE173257T1 (de) 1998-11-15
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DE69414554T2 (de) 1999-06-17
IL108865A (en) 2000-07-16
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SK281005B6 (sk) 2000-10-09
ES2126099T3 (es) 1999-03-16
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ZA941542B (en) 1995-09-04
AU694415B2 (en) 1998-07-23
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